Peripheral Mitochondrial Dysfunction: A Potential Contributor to the Development of Metabolic Disorders and Alzheimer's Disease.
Peripheral Mitochondrial Dysfunction: A Potential Contributor to the Development of Metabolic Disorders and Alzheimer's Disease.
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阿尔茨海默病（AD）是一种进行性疾病，其中痴呆症状逐渐恶化。AD的原因很复杂，其特征在于大脑中的变化导致两种蛋白质（淀粉样蛋白β和tau）的积累，分别形成称为斑块和缠结的结构。确定AD的起始和进展的机制是具有挑战性的。因此，关于其起源提出了多种假说，表明线粒体功能障碍或代谢紊乱或两者兼而有之。代谢性疾病如糖尿病与AD之间的关系已被广泛研究，最近，通过抗糖尿病干预预防AD成为一种有前途的策略。此外，来自外周线粒体功能障碍的氧化应激和炎症也被认为是AD发病机制的替代因素;然而，其机制仍然未知。在这篇综述中，我们总结了代谢紊乱，线粒体功能障碍和AD之间可能的相互作用，并因此，未来的治疗策略，可以针对外周线粒体损伤，以预防和/或治疗AD。阿尔茨海默病（Alzheimer's disease，AD）是一种以脑内神经元功能丧失和最终死亡为特征的进行性神经退行性疾病。多项研究强调了线粒体参与神经退行性疾病的发生和发展。线粒体对于ATP的产生、生物能量学过程、钙稳态的调节和自由基清除是必不可少的。破坏这些过程中的任何一个都被认为是常见神经退行性疾病（尤其是AD）发病机制的主要贡献者。一些纵向研究已经证明2型糖尿病（T2 D）是导致AD的痴呆起源的风险因素。尽管新兴的研究表明，抗糖尿病干预是AD预防和治疗的一个有前途的选择，但抗糖尿病药物的临床试验结果在AD中并不有效。有趣的是，据报道，线粒体功能缺陷也会导致代谢紊乱的发生，包括肥胖和T2 D。线粒体功能障碍的最普遍后果包括炎症分子和活性氧（ROS）的产生，其促进代谢障碍和神经退行性疾病的发作和发展。目前的证据表明外周线粒体功能受损与原发性AD病理学相关;然而，其机制尚不清楚。因此，在这篇综述中，我们讨论如果线粒体功能障碍介导的代谢紊乱与AD的发展有潜在的联系，那么解决外周线粒体功能障碍在预防代谢紊乱相关的AD病理方面会有更好的治疗效果。
Alzheimer’s disease (AD) is a progressive disease, where dementia symptoms gradually worsen. The causes of AD are complex and are characterized by changes in the brain that lead to the accumulation of two proteins, amyloid beta and tau, forming structures called plaques and tangles, respectively. It is challenging to identify the mechanisms for the initiation and progression of AD. Therefore, multiple hypotheses have been proposed regarding its origin, suggesting mitochondrial dysfunction or metabolic disorders, or both, playing a role. The association of metabolic diseases such as diabetes with AD has been widely studied and more recently, emerged as a promising strategy for AD prevention through anti-diabetic intervention. Further, oxidative stress and inflammation derived from peripheral mitochondrial dysfunction have also been suggested as alternative contributors of AD pathogenesis; however, the mechanism is still unknown. In this review, we summarize the possible interactions between metabolic disorders, mitochondrial dysfunction and AD, and, accordingly, future therapeutic strategies that could target peripheral mitochondrial impairment to prevent and/or treat AD. Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by loss of function and eventual death of neurons in the brain. Multiple studies have highlighted the involvement of mitochondria in the initiation and advancement of neurodegenerative diseases. Mitochondria are essential for ATP generation, bioenergetics processes, the regulation of calcium homeostasis and free radical scavenging. Disrupting any of these processes has been acknowledged as a major contributor to the pathogenesis of common neurodegenerative diseases, especially AD. Several longitudinal studies have demonstrated type 2 diabetes (T2D) as a risk factor for the origin of dementia leading towards AD. Even though emerging research indicates that anti-diabetic intervention is a promising option for AD prevention and therapy, results from clinical trials with anti-diabetic agents have not been effective in AD. Interestingly, defective mitochondrial function has also been reported to contribute towards the onset of metabolic disorders including obesity and T2D. The most prevalent consequences of mitochondrial dysfunction include the generation of inflammatory molecules and reactive oxygen species (ROS), which promote the onset and development of metabolic impairment and neurodegenerative diseases. Current evidence indicates an association of impaired peripheral mitochondrial function with primary AD pathology; however, the mechanisms are still unknown. Therefore, in this review, we discuss if mitochondrial dysfunction-mediated metabolic disorders have a potential connection with AD development, then would addressing peripheral mitochondrial dysfunction have better therapeutic outcomes in preventing metabolic disorder-associated AD pathologies.